Leptomeningeal carcinomatosis (LMC) is a devastating terminal condition with no effective treatment. Metastatic breast cancer (BC) is responsible for a significant number of cases. The median survival of a treated patient is abysmally low and currently stands at less than 6 months from the time of diagnosis. LMC is challenging because it rapidly progresses and it involves the entire neuraxis. Due to the extent of disease, the toxicity of chemotherapy is a major concern in LMC and external beam radiotherapy is often used locally only for palliative relief. No good solution currently exists to block the subarachnoid expansion of aggressive leptomeningeal metastases which are reliant on certain molecular drivers including a very specific subset of integrins (i.e., the ?v an ?5 integrin subclasses) for their dissemination. Importantly, these integrins are not expressed in the surrounding normal brain and spinal cord tissue. In this application, we propose to explore a radically new therapeutic strategy for LMC that combines targeted radiotherapy with the pharmacological reprograming of the tumor immune cell microenvironment. This relies on the precision delivery of minute 131I radionuclide doses into leptomeningeal metastases administered via a pan-integrin targeted human disintegrin polypeptide called DTI15. We hypothesize that this event will elicit a DNA-damage response and the upregulation of tumor cell surface markers that are recognized by tumor infiltrating NK cells. We further hypothesize that the anergic state of tumor infiltrating NK cells can be overcome with global TAM receptor inhibitors (TAMi), which represents the second component of our therapeutic strategy. This will result in a sustained tumor cytolytic innate immune response in LMC. Key to this approach is the property of disintegrins such as DTI15 to bind integrins with high specificity and affinities in the low nM range, which leads to rapid receptor internalization. This creates a unique therapeutic solution for precision radionuclide delivery into LMC metastases. Due to its extreme stability, DTI15 can be efficiently labeled with radionuclides such as 124I (positron emitting) or 131I (beta emitting) for multimodal imaging and radiotargeted destruction of metastatic foci. However, here we propose to evaluate the delivery?via DTI15?of much lower (sublethal) radiation doses in combination with immunotherapy, which is expected to be much better tolerated by the patients with LMC. To mechanistically test this approach, in Specific Aim 1, we will evaluate the effects ionizing radiation in combination with TAMi on tumor infiltrating immune cells in a 3D co-culture in vitro model of LMC. In Specific Aim 2, we will conduct imagistic and dosimetry studies in animal models of LMC with 124I- DTI15 (quantitative PET), followed by efficacy studies with sub-radioablative doses of 131I-DTI15 in combination with TAMi to determine the anti-tumor mechanism and the toxicity profile of this novel approach in LMC.